Edward R. Thornton

Apparent chelation control in aldol reactions of chiral (Me2CHO)3Ti-enolates

Directed aldol reactions of chiral (Me2CHO)3Ti-enolates give the opposite diastereofacial selectivity compared with the corresponding boron enolates. This stereochemical reversal is best explained if the Ti reactions involve chelation (not possible with boron, and previously thought to be unfavorable with (Me2CHO)3Ti-enolates). Changing the solvent from THF to diethyl ether significantly enhances the hypothesized chelation effect. Use of Ti or boron thus permits convenient synthesis of either product enantiomer, starting from that one chiral auxiliary whose configuration is readily and inexpensively derived from natural sources.

13C NMR chemical shift titration of metal ion-carbohydrate complexes. An unexpected dichotomy for Ca+2 binding between anomeric derivatives of N-Acetylneuraminic acid (1)

Abstract The complexation of Ca +2 with N -Acetylneuraminic acid, its methyl ester and its α and β methyl glycosides was studied by titrating the 13 C NMR chemical shifts with added CaCl 2 . These studies demonstrate that the strong Ca +2 binding previously observed in the β anomer is not shared by the biochemically relevant α anomer. The strong β complex uses three oxygen atoms as binding sites for Ca +2 but these oxygens are not involved in the weak binding of the α anomer.

Very high diastereofacial selectivities in convenient titanium—mediated aldol reactions

Very high (> 99%) diastereofacial selectivities in aldol reactions of a chiral titanium enolate with a variety of aldehydes can be conveniently achieved. The ease of preparation of -Ti(OCHMe2)3 enolates, low cost, low toxicity, and ease of work-up make this a very useful method for synthesis of chirally pure substances.

A theoretical interpretation of isotope effects in mixtures of light and heavy water—II

Abstract Solvent isotope effects for H 2 OD 2 O mixtures and for ionic hydration equilibria in such mixtures can be calculated from the structure difference between D 2 O and H 2 O and that between HDO and H 2 O and the relative amounts of the three waters. The behavior of acids in H 2 OD 2 O mixtures is considered in detail. Dissociation constants of acetic acid are calculated over the complete range of deuterium concentrations and found to agree with the experimentally determined ones. The Gross equation for the dependence of isotope effect on mole fraction of deuterium for acid-catalyzed reaction of substrates S proceeding via SL + transition states (LH or D) is derived from first principles.

Asymmetric aldol reactions. Mechanism of solvent effect on stereoselectivity is specific, stoichiometric binding of tetrahydrofuran to a chiral titanium enolate

Abstract Solvent plays an important role in aldol reactions of an acyloxazolidinone-derived titanium enolate. Diethyl ether produces nearly fivefold higher diastereofacial selectivity than THF. We now show that this strong solvent effect arises from stoichiometric binding, most probably to the titanium, of THF in the transition structure, whereas ether is not bound. These mechanistic results indicate that THF lowers the selectivity by interfering with chelation control, which is highly preferred in ether. Implications include the possibility of using other ethers to improve chelation/nonchelation control still more, or even use of chiral ethers as chiral controller groups or adjuncts.

Conformational model for asymmetric Diels-Alder reactions with chiral dienes

Abstract 1-( O -methylmandeloxy)dienes have significant advantages for asymmetric Diels-Alder reactions, and we now show that high (90%) diastereofacial selectivities can be obtained with these dienes, permitting considerable choice as to dienophile and the presence of additional functionality. We present experimental support, including X-ray structures showing the conformations of three Diels-Alder adducts, for a transition state model which explains the origin of these selectivities. The distinctive characteristics of this model are that the phenyl group is nearly perpendicular to the ester CO, i.e., the PhCCO dihedral angle is near 90°, and that the methoxy group is close to the carbonyl oxygen. These features may have wider applications for chiral control by α-chiral ester groups in other types of reactions. Our results should renew interest in the use of chiral 1-acyloxydienes.

Asymmetric diels-alder reactions. Inverse electron demand reactions of esters of 3-hydroxypyran-2-one with vinyl ethers: use of high pressure to avoid decarboxylation of adducts

Abstract Asymmetric inverse electron-demand Diels-Alder reactions of esters of 3-hydroxypyran-2-one with vinyl ethers proceed under high pressure at ambient temperature, making isolation of the synthetically useful bicyclic adducts feasible. Investigation has revealed that the desired adduct can be synthesized with diastereofacial selectivity, up to 88:12, by reaction of the acetate of 3-hydroxypyran-2-one with chiral 8-(3.5-dimethylphenyl)menthyl vinyl ether.

Steric influence of silyl groups in titanium- and lithium-mediated aldol condensations

Reactions of lithium enolates of α-silyloxyketones 1a, 1b, 2a, and 2b with benzaldehyde yield opposite diastereoselection depending upon the size of the silyl group, but all four titanium enolates lead to high diastereofacial selectivities. These results implicate a nonchelated transition structure which is insensitive to the steric size of the silyl group for the titanium-mediated aldol reactions. Ketone 1a is shown to give high selectivities for the two opposite syn adducts (99:1 with Ti; 10:90 with Li). Because it is readily prepared in monochiral form, 1a may offer advantages as a chiral precursor for preparation of either product stereochemistry, as desired.

Asymmetric aldol reactions of an α′-benzoyl titanium enolate

Abstract Diastereofacial selectivities of 97–99.7% can be conveniently obtained in aldol reactions of the chiral titanium enolate derived from the ketone C 2 H 5 COCH(OCOPh) cyclo -C 6 H 11 , with representative aldehydes.

α′-Benzoyloxy and α′-methoxymethoxy lithium enolates giving opposite diastereofacial selectivities in aldol reactions. Use of (probable) extended chelation for reversal of stereoselectivities

Abstract The Li enolates of α-benzoyloxy and α-methoxymethoxy ketones 1a and 1c afford nonchelation and chelation aldol products, respectively, both with usefully high diastereofacial selectivities. Evidence suggests that transition state chelation of the benzoyl C=O is responsible for the observed “nonchelation” stereoselectivity of 1a .